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Background Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug–drug interactions compared with other triazoles. Methods In our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose. Results Sixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations. Conclusions ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies. Clinical Trials Registration NCT03019939.

Background E. faecalis (Efc) isolates are usually susceptible to ampicillin (AMP). AMP-based regimens are the standard of care for enterococcal infections, although other antibiotics are often used as definitive treatment. We thus compared outcomes of patients with cancer and Efc bacteremia treated with AMP-containing (ACR) and non-AMP-containing antibiotic regimens (NACR). Methods A multicenter, prospective, observational cohort study conducted at MD Anderson Cancer Center, Henry Ford Hospital, and Memorial Hermann Health System. Eligible patients were ≥ 18 years old, diagnosed with cancer, and had at least one Efc bloodstream isolate collected from 12/2015 to 12/2018. Patients with polymicrobial infections were excluded. Patients were divided into two groups: i) ACR and ii) NACR. ACR included patients who received AMP at any time during treatment; other antimicrobials were permitted. NACR patients did not receive AMP at any time. The primary outcome compared desirability of outcome ranking (DOOR) between ACR and NACR at day 14. The DOOR consisted of six hierarchical levels: 1 - death; 2 - inpatient without microbiological cure (MC) and with acute kidney injury (AKI); 3 - inpatient without MC and without AKI; 4 - inpatient admitted with MC and with AKI; 5 - inpatient with MC and without AKI; 6 - alive and discharged. Comparison of DOORs between ACR and NACR was performed using inverse probability of treatment weighted (IPTW) ordered logistic regression. Results Seventy-one patients were included (ACR, n = 35; NACR, n = 36). No difference was seen in DOORs at day 14 between ACR and NACR (odds ratio [OR] 1.14, 95% Confidence Interval [CI] 0.45 – 2.92, p=0.78). No difference was observed for all-cause mortality at day 14 (OR 0.6, 95% CI 0.09 – 3.77, p=0.58) or day 30 (OR 0.42, 95% CI 0.09 – 1.94, p=0.27). Patients treated with ACR received a lower median duration of other antibiotics at any point during treatment compared to NACR: daptomycin (2 v 4 days) vancomycin (2 v 4 days), and linezolid (1 v 2 days). Conclusion Patients with cancer and Efc bloodstream infections had similar outcomes when treated with ACR and NACR. ACR were associated with less use of broad-spectrum antimicrobials. Future research should focus on the ecologic impact of use of NACR. Disclosures Marcus Zervos, MD, Melinta Therapeutics (Grant/Research Support) Cesar A. Arias, MD, MSc, PhD, FIDSA, Entasis Therapeutics (Scientific Research Study Investigator)MeMed (Scientific Research Study Investigator)Merck (Grant/Research Support)

Background Mold-active antifungal prophylaxis (ppx) is recommended in neutropenic patients with newly diagnosed AML or MDS. ISAV is an extended spectrum triazole with superior tolerability, reliability of absorption, fewer drug–drug interactions, lack of QTc prolongation or need for therapeutic drug monitoring, approved for the treatment of invasive aspergillosis (IA) and mucormycosis. NCT03019939 is an investigator-initiated, phase 2 trial of PAP with ISAV in patients with AML/MDS. Methods Treatment-naïve adult patients with AML or MDS initiating remission-induction chemotherapy (RIC) received ISAV per the dosing recommendations in the United States label until recovery from neutropenia (neutrophils (ANC) ≥ 0.5 × 109/L) and attainment of complete remission (CR), occurrence of proven or probable invasive fungal infection (IFI, EORTC/MSG criteria), or for a maximum of 12 weeks. The primary endpoint was incidence of proven/probable IFI during the study period (up to 30 days from the last dose of ISAV). Results 67 patients were enrolled (April 28, 2017 to February 14, 2019) and 60 patients were eligible for assessment (median age 67 years, 57 patients with AML, median ANC on enrollment was 660). Reasons for study completion were achievement of CR with ANC recovery (n = 35), completion of 12 weeks of PAP (n = 9), possible IFI (n = 7), investigator decision (n = 3), death (n = 2, 1 disease progression, 1 cardiac arrest), proven/probable IFI (n = 3), and mild transaminitis, possibly ISAV-related (n = 2). The median durations of neutropenia and ISAV ppx were 33 (7–86) and 31 (7–86) days, respectively. One microbiologically-proven (gluteal abscess due to Candida glabrata) and 2 cases of probable breakthrough IFIs (probable IA with positive galactomannan) occurred (IFI incidence 5%). ISAV trough serum concentrations were available in 31 patients on both day 8 (median 3.74 µg/mL, 2.03–7.65) and day 15 (median 4.10 µg/mL, 2.17–9.25), and were not significantly different. Conclusion ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC, with a breakthrough (proven/probable) IFI rate of 5%. ISAV serum levels were adequate in patients with AML/MDS undergoing RIC. Pharmacological features make ISAV attractive for PAP in the era of recently approved or emerging small-molecule AML therapies. Disclosures All authors: No reported disclosures.